In an AMI, neutrophil counts are found to be significantly raised as a result of mobilization from the bone marrow, and this is used as a predictor of adverse outcomes and mortality (25). Significant neutrophil recruitment occurs in which their phagocytic functions serve to contribute to the clearance of debris. However, the vast array of hydrolytic, oxidative, and pore-forming molecules released by an overabundance of phagocytic neutrophils, alongside their delayed removal from the infarct site, end up causing significant collateral heart tissue destruction (7, 26). Circulating neutrophil counts peak within 1–3 days and drop after day 4 (Figure 1). Neutrophils are recruited to the infarcted area within hours following myocardial IR injury. In 2016, Ma et al. further showed that neutrophils harvested from the heart on day 1 post-MI were N1 neutrophils (pro-inflammatory), that express highly pro-inflammatory mediators, whereas those isolated between days 5–7 were N2 (anti-inflammatory) neutrophils (8, 27). Strategies such as neutrophil CD11/CD18 inhibition have been effective in reducing MI size in animal models (28). Recent studies highlighted neutrophils as a source of S100A8/A9, and its timely pharmacological inhibition was shown to improve cardiac function (18, 29).

Following an AMI, monocytes from the bone marrow and spleen are mobilised into the circulation and drawn to the injury site by chemotaxis. Peripheral monocytosis serves as an indicator of potential adverse LV remodeling (30). Murine studies showed that pro-inflammatory classical, or Ly6C^high monocytes, peak in numbers between days 3 and 4. These monocytes then differentiate into pro-inflammatory M1 macrophages, responsible for producing proteases (MMPs), cytokines (IL-1, IL-6, TNF-α, IFN-γ), chemokines (CCL2), and growth factors, aiding in debris clearance and initiating wound healing (31). Subsequently, the recruitment of anti-inflammatory non-classical, or Ly6C^low monocytes, takes place, peaking around day seven (8, 24). As M1 macrophage numbers diminish, M2 anti-inflammatory macrophages take over, orchestrating wound healing in the subsequent reparative phase (Figure 1). However, a prolonged presence of M1 macrophages can intensify the pro-inflammatory phase, aggravate damage beyond the initially infarcted area, and lead to adverse LV remodeling. This underlines the potential cardioprotective benefits of pharmacologically inhibiting M1 macrophages (8, 32). Furthermore, monocytes can differentiate into antigen-presenting dendritic cells, initiating the adaptive immune system through the production of chemokines and cytokines (IFN-γ, IL-6), which in turn activate T cells (9, 33).

Lymphocytes are key players in the cell-mediated cytotoxic innate immune response, with various subsets actively involved. In animal models, both T and B lymphocyte subsets have been observed infiltrating the injury site. Following an AMI, patients display an increase in pro-inflammatory CD4⁺ Th1 and cytotoxic CD8⁺ T cells and a reduction in anti-inflammatory and protective CD4⁺ Th2 cells. The prolonged presence of these detrimental lymphocytes is linked to poorer patient prognosis (34, 35). Moreover, an increase in peripheral B cells has been noted in AMI cases, with mature B cell infiltration peaking around day five. Zouggari et al., (36), demonstrated that B cells release CCL7, which mobilizes bone marrow Ly6C^high monocytes to the injury site, exacerbating tissue damage. They also demonstrated a potential therapeutic role following B cell genetic depletion, as evidenced by reduced systemic inflammation, LV remodeling and MI size (36). Additionally, natural killer (NK) cells and their receptor expressions are significantly reduced following an MI, with recent studies indicating a protective role for these cells in atherosclerosis (37).

Platelets are well-known for their critical role in thrombosis. Recently, they have also been identified as key players in inflammation, contributing to the innate immune response. They aggregate in injured areas, localising the inflammatory response and aiding in the formation of a provisional matrix. During inflammatory events like AMI or post-reperfusion, platelets release inflammatory mediators such as cytokines, chemokines, and platelet-derived growth factor (PDGF). Their pro-inflammatory activities include upregulating ICAM-1, VCAM-1, and selectins on leukocytes, triggering ROS production, activating macrophages and cytotoxic lymphocytes, and enhancing circulating microparticle production (38, 39). Studies also shows a link between innate immunity, platelet activation, and coagulation, known as immunothrombosis. Its abnormal activation in cardiovascular diseases increases the risk of cardiovascular events, including AMI (40). Extracellular DNA, a trigger for immunothrombosis in AMI, has been identified, with studies highlighting the potential of DNase I treatment to reduce infarct size in myocardial ischemia models (41). Moreover, platelets can influence leukocyte functions by forming platelet-leukocyte (P-L) aggregates through P-selectin/PSGL-1 interactions. An increase in P-L aggregates in peripheral blood has been noted post-AMI, suggesting their potential as early biomarkers for MI (42). Additionally, targeting these P-L aggregates with anti-platelet therapies has shown effectiveness in reducing inflammation and subsequent complications in MI patients.

In COPD patients, high neutrophil counts correlate with poor outcomes and increased mortality (49, 50). However, these neutrophils exhibit compromised chemotaxis and release inflammatory mediators that contribute to alveolar damage (Figure 1) (51, 52). Both neutrophils and macrophages are key sources of MMPs, which are implicated in the breakdown of the extracellular matrix (ECM), airway obstruction, remodeling, and the development of emphysema (53, 54). MMP-12, in particular, is crucial for emphysema formation, as evidenced by MMP-12 deficient mice not developing emphysema post-cigarette smoke (CS) exposure (55). In COPD patients, MMP-2 and MMP-9 are potential biomarkers, with the highest expression levels observed in severe COPD cases (56). Specifically, the MMP-9 to tissue inhibitors of MMP-1 (TIMP-1) ratio has been linked to an increased mortality risk, indicating that targeting MMP-9 may help reduce this risk (57). Additionally, MMP-2 is implicated in ECM remodelling (58). Neutrophil elastase (NE), a neutrophil-derived serine protease, also plays a significant role in ECM degradation, influencing mucus secretion and fibroblast proliferation, which further contribute to airway obstruction and bronchial fibrosis (59, 60). Mice deficient in NE showed resistance to emphysema development in a CS exposure model (61). Moreover, excessive formation of neutrophil extracellular traps (NETs) has been associated with alveolar destruction (62).

In COPD, heightened macrophage recruitment within airways and lungs is a predictor of alveolar damage and disease progression (63). Pro-inflammatory M1 macrophages, prevalent in emphysematous regions, release a variety of inflammatory mediators. These mediators drive alveolar destruction via autocrine and paracrine pathways (Figure 1) (64–66). IL-1β and TNF-α intensify inflammation and lung tissue damage by upregulating neutrophilic cytokines and MMPs (Table 1) (5, 11). Mice lacking the IL-1 receptor exhibited resistance to emphysema and small airway remodeling in a CS exposure model (6). However, a clinical trial using an anti–IL-1R1 monoclonal antibody did not enhance lung function or quality of life in COPD patients (67). Recent studies have also delved into the role of the IL-36 sub-family in COPD (68, 69). IL-36 cytokines, primarily expressed in small airway cells, macrophages, and fibroblasts, are implicated in neutrophil recruitment, mucus hypersecretion, emphysema, and airway remodeling. Notably, COPD patients exhibit exacerbated symptoms due to a reduction in endogenous IL-36Ra in macrophages (15). IL-8, produced by macrophages, small airway cells, and endothelial cells, is also involved in mucus secretion and airway obstruction (70). Mice deficient in the IL-8 receptor, CXCR2, demonstrated protection against lung inflammation and DNA damage in a CS exposure model (71). IL-18 is notably elevated in the lungs of COPD patients, particularly in alveolar macrophages and epithelia, and its serum levels are higher compared to smokers and nonsmokers (72). This increase negatively correlates with pulmonary function and is linked to enhanced IFNγ production in severe COPD, contributing to remodeling responses (73). Similarly, IL-32 levels correlate positively with COPD severity, suggesting its potential as a biomarker for disease severity (74).

COPD activates the adaptive immune system, characterised by the presence of B, T, and T-helper type 17 (Th17) cells, and a decrease in regulatory T-cells (Tregs) in the airways (Figure 1) (75). The progression of the disease sees the formation of lymphoid follicles, comprising B and T-cells, in the walls of small airways (76). Mice deficient in T and B-cells exhibited significantly reduced airway remodeling (77). A recent study noted an increased ratio of CD8⁺ to CD4⁺ cells in COPD patients, indicating a shift towards Th1/Tc1 dominance, which was associated with COPD exacerbation (78). Th17 cells, prominent producers of pro-inflammatory IL-17, are elevated in advanced COPD stages and contribute to CS-induced lymphoid neogenesis (13). Importantly, mice lacking the IL-17 receptor were protected from airway inflammation and fibrosis (14).

Platelets contribute to COPD-related inflammation through lung elastin breakdown and the formation of platelet aggregates (79). Elevated platelet counts and reactivity are associated with increased lung inflammation, reduced lung function, and greater disease severity in COPD patients (80). COPD is linked to a hypercoagulable state marked by raised coagulation factor levels, leading to a prothrombotic effect. This state features increased fibrinogen and coagulation factors, alongside decreased coagulation inhibitors. Systemic and neutrophilic inflammation contribute to these prothrombotic changes (81). While the exact role of immunothrombosis in COPD is still under investigation, it's believed to contribute to pathogenesis, potentially through NETs (82).

In COPD, mast cells and eosinophils play significant roles in inflammation. Changes in mast cell populations in COPD patients include an increase in connective tissue mast cells (MC_TC) and a decrease in mucosal mast cells (MC_T), which are associated with airway remodeling and reduced lung function (83). The molecular mechanisms of mast cell involvement in COPD are still under investigation, but current hypotheses include their role in neutrophil recruitment, mucus hypersecretion through mast cell chymase, and tissue damage via enzymes like elastase, tryptase, and chymase (84). Eosinophil counts and related proteins may rise in certain COPD patients, particularly those with concurrent asthma (85, 86), although other studies report no significant increase or activation of eosinophils (86).

A hallmark of COPD is the occurrence of acute exacerbations, typically triggered by infections (bacterial or viral) or environmental factors (pollutants). These exacerbations are characterised by a sudden worsening of respiratory symptoms and an elevated inflammatory response. Consequences include aggravated mucus hypersecretion, bronchoconstriction, impaired gas exchange, respiratory muscle fatigue, hypoxemia, hypercapnia, respiratory acidosis, and compromised vascular perfusion. The frequency of AE-COPD is closely associated with declining lung function and increased mortality (87). Neutrophils predominantly mediate the inflammatory response in AE-COPD, although eosinophilia has also been linked to AE-COPD and its risk (88, 89). Elevated neutrophil counts have been documented in bronchoalveolar lavage fluid (BALF), bronchial walls, pulmonary microcirculation, and airways (90). During AE-COPD, various inflammatory mediators show increased levels compared to stable COPD, including serum CXCL8, e-selectin, TNF-α, IL-6, and more recently, MMP-9, IL-1β, IL-8, IL-17, IL-18, and S100A8/A9 (Table 1) (91–93). Serum IL-8 has proven more sensitive than TNF-α or IL-6 in predicting AE-COPD (12). Additionally, a clinical correlation has been established between increased NK cell presence and AE-COPD (94). In a mouse model of AE-COPD (CS exposure and viral infection), NK cells were found to produce more IFN-γ (95). Furthermore, evidence suggests that inflammatory mediators from the lungs can spillover into systemic circulation, causing chronic, non-resolving, low-grade systemic inflammation. This condition potentially leads to cardiovascular comorbidities, muscle weakness, and other systemic issues (21). The mechanism of this spillover is under debate. Currently, it is hypothesized to involve local activation of inflammatory pathways, elevating various inflammatory markers such as IL-6, IL-1β, TNF-α, CRP, and inflammatory cells in the peripheral blood (21, 96). Furthermore, the mobilization of inflammatory cells from the bone marrow, driven by factors like granulocyte-colony-stimulating factor (G-CSF), is believed to contribute to the increased presence of these cells in peripheral blood (97, 98). AE-COPD are also linked to an inflammation-driven prothrombotic state, featuring elevated platelet-monocyte aggregates, increased platelet count, endothelial activation, and heightened plasmatic prothrombotic markers (46).

The IL-1 superfamily (IL-1F), encompassing eleven cytokines, plays a pivotal role in modulating the innate immune response. This family includes both pro-inflammatory and anti-inflammatory cytokines that influence integrin expression on target cells and stimulate cytokine release from stromal cells. The pro-inflammatory members are IL-1α, IL-1β, IL-18, IL-36α, IL-36β, IL-36γ, and IL-33. The anti-inflammatory cytokines are divided into immunosuppressive (IL-37 and IL-38) and antagonist cytokines (IL-1Ra, which antagonizes IL-1α and IL-1β, and IL-36Ra, targeting IL-36α, IL-36β, and IL-36γ). Except for IL-1Ra, all members of the IL-1 family are initially produced as precursor proteins, requiring proteolytic cleavage to become active, mature proteins (120). IL-1 cytokines (IL-1α and IL-1β) have garnered significant attention; these agonists, located in the cytoplasm, are expressed in various cells, including neutrophils, monocytes, and macrophages. However, some members, like the IL-36 cytokines, have been recently discovered, and research on their functions remains limited (121). IL-1F cytokines are often the earliest and most upstream responders to injury, making them promising targets for managing inflammatory disorders (122). Given their critical role in mediating inflammation, IL-1F members could be key to understanding and addressing myocardial and pulmonary disturbances.

Experimental models that target IL-1 in myocardial IR injury have shown promise. Toldo et al. (123) reported that anakinra, a recombinant human IL-1 receptor antagonist (IL-1Ra), significantly reduced infarct size and improved LV ejection fraction in mice following myocardial IR injury (123). Likewise, a study in rat hearts indicated that IL-1Ra overexpression protected against IR injury by attenuating cell death and reducing infarct size through its anti-inflammatory properties on neutrophils (124). Clinical studies using anakinra or canakinumab, an IL-1β monoclonal antibody, in STEMI or NSTEMI patients have been mixed. Morton et al. (125) conducted a double-blinded randomized phase II trial with anakinra in NSTEMI patients, finding decreased CRP levels but increased adverse outcomes (recurrent MI, stroke, and death) over one year (8, 125). Conversely, the CANTOS trial by Ridker et al. (126) demonstrated that canakinumab significantly reduced nonfatal MI, stroke, or cardiovascular death in high-risk patients over 3.7 years (126). This was the first major clinical trial to show that targeting inflammation can confer modest cardiovascular benefits in very high-risk patients and has been credited with providing an exciting glimpse at the potential for using anti-inflammatory therapies for treating cardiovascular diseases.

In CS exposure models, IL-1 inhibition also showed effectiveness. Castro et al. (127) found that an anti-IL-1β antibody significantly reduced CS-induced lung inflammation (127). Churg et al. (6) reported protection against emphysema and airway remodeling in IL-1R knockout mice exposed to CS (6). A phase I clinical study by Hernandez et al. (128) using anakinra in healthy volunteers exposed to inhaled lipopolysaccharide (LPS) showed reduced airway neutrophilia and cytokine levels (IL-1β, IL-6, and IL-8) (128). In a phase II trial, Calverley et al. (67) tested MEDI8968, an IL-1R1 monoclonal antibody, in moderate-to-severe COPD patients, finding initial inflammation reduction but no significant changes in AE-COPD rate, lung function, or quality of life compared to placebo (67). Overall, this trial suggested potential benefits for COPD patients with high neutrophil counts, though current serum biomarkers might not adequately identify these patients.

IL-36, a relatively recent member of the IL-1 family discovered about two decades ago, plays a key role in pro-inflammatory mediator production, immune cell activation, and antigen presentation (129). As well as amplifying IL-1 effects, IL-36 is also a mediator of inflammation in its own right. Indeed, its critical role in psoriasis, equalling if not surpassing that of IL-1, is well established with emerging roles in Crohn disease and rheumatoid arthritis recently identified (130–132). Research into IL-36 as a pro-inflammatory cytokine in various inflammatory diseases is extensive, but studies in AMI or COPD are more recent.

In experimental models of myocardial IR injury, inhibiting IL-36R has shown success. In 2019, Wei et al. found that administering recombinant mouse IL-38 in mice post-IR injury reduced inflammation, cardiac fibrosis, and myocardial injury, suggesting IL-38 could benefit cardiac remodeling after MI (133). More recently, we demonstrated that treatment with IL-36Ra in mice with myocardial IR injury significantly reduced infarct size and neutrophil recruitment, and improved blood flow. The mechanism involved attenuating endothelial and cardiac myocyte oxidative damage and VCAM-1 expression (16, 134). In the context of COPD, while the IL-36/IL36R pathway's pro-inflammatory role in the lungs is well recognized, its protective potential is still emerging. Baker et al. (15) reported reduced virally induced IL-36-mediated inflammation in COPD using IL-36Ra (Spesolimab) or an IL-36R blocking antibody. This was mechanistically explained by blocking the crosstalk between virally stimulated COPD small airway epithelial cells and small airway fibroblasts (15). Additionally, their 2021 study showed that IL-36R knockout mice had diminished lung inflammation and neutrophil recruitment in a CS exposure model (17). These findings suggest a novel role for IL-36 in both myocardial IR injury and COPD and necessitate further exploration in a comorbidity model.