Studies indicate that macrophages participate in the pathogenesis of rosacea by eliciting inflammation associated with innate immune responses. When the skin is stimulated by factors such as microorganisms and their products, ultraviolet radiation, and psychological stress, keratinocytes become activated and release LL-37, which in turn activates TLR2 on macrophages, upregulating the expression of kallikrein-related peptidase 5 (KLK5). Subsequently, KLK5 cleaves hCAP18 into its active form, LL-37 (28, 29). LL-37 not only directly opposes invading pathogens (30), but also activates signaling pathways such as janus kinase (JAK)/STAT, nuclear factor-kappa B (NF-κB), and NOD-like receptor family pyrin domain containing 3 (NLRP3), thereby promoting the production of pro-inflammatory cytokines like IL-1β, IL-6, and TNF-α, inducing and maintaining inflammatory responses and angiogenesis (31–33). Concurrently, LL-37 produced by macrophages binds to TLR2 through an autocrine mechanism, activating the mammalian target of rapamycin complex 1 (mTORC1) pathway. This leads to an increased production of LL-37 and amplification of the inflammatory response, forming a positive feedback loop (34). Additionally, macrophages upregulate the gene expression of NLRP3 and pro-IL-1β via the TLR2/myeloid differentiation primary response gene 88 (MyD88)/NF-κB pathway, facilitating the recruitment and activation of cysteine-aspartic acid protease-1 (caspase-1), which induces pyroptosis and the release of IL-1β and IL-18 (35, 36). As a pivotal inflammatory cytokine, IL-1β upregulates the expression of cytokines such as IL-8, TNF, and cyclooxygenase (COX)-2 (37). Among these, IL-8 promotes pustule formation in PPR skin lesions by mediating neutrophil chemotaxis, TNF mediates inflammatory cascades, promoting papule formation and the sensation of burning, and COX-2 catalyzes the production of prostaglandin (PG)E2, inducing pain (38–40) ( Figure 1 ).

Studies have found that there is a significant infiltration of CD4+ T cells in the skin lesions of patients with rosacea, predominantly comprising helper T cells (Th) 1 and Th17 cells, suggesting that adaptive immune responses also play a role in the pathogenesis of rosacea (24, 41). Macrophages, as professional antigen-presenting cells, process and present antigens to T cells by phagocytosis or recognition of microbes and their products through TLRs, inducing the occurrence of adaptive immune responses (42). Concurrently, M1 macrophages facilitate the activation and proliferation of T cells through the interaction of their surface markers CD40, CD80, and CD86 with co-stimulatory molecules on the surface of T cells (43). Furthermore, IL-12 secreted by macrophages induces the differentiation of Th0 cells into Th1 cells (44, 45), while IL-1β and IL-6 induce the differentiation of Th0 cells into Th17 cells (46, 47). Correspondingly, Th1 cells stimulate the polarization of macrophages towards the M1 phenotype by secreting type 1 inflammatory cytokines such as IFN-γ and TNF-α (48). Th17 cells, on the other hand, secrete IL-17 to stimulate local tissue cells to produce chemokines, recruiting monocytes and neutrophils to the lesion site, thereby exacerbating local inflammation (49, 50). Therefore, in the pathogenesis of rosacea, a positive feedback loop forms between the innate immune system represented by macrophages and the adaptive immune system mediated by CD4+ T cells, continuously amplifying the immune inflammatory response and promoting disease progression.

Studies found that under inflammatory conditions, M1 macrophages activate STAT3 and NF-κB signaling pathways through an IL-1β autocrine loop. In an IL-1β-dependent manner, they bind to the nuclear VEGFA promoter, thereby promoting the transcription and expression of VEGFA and participating in angiogenesis (51, 52). Additionally, pro-inflammatory cytokines such as IL-1, IL-6, and TNF-α released by macrophages can also upregulate the expression of VEGF (53). Among them, IL-6 induces corneal fibroblasts to produce VEGF by activating the STAT3 signaling pathway, stimulating corneal neovascularization, and participating in the occurrence and development of OR (31, 54). Concurrently, VEGF induces endothelial cells to produce chemokines such as monocyte chemotactic protein (MCP)-1 and IL-8, as well as adhesion molecules such as intercellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM), recruiting and activating inflammatory cells such as the monocytic macrophage lineage and neutrophils, amplifying the inflammatory response (55–57). Therefore, VEGF is also considered a key molecule linking immune inflammation and angiogenesis.

Furthermore, M1 macrophages specifically express inducible nitric oxide synthase (iNOS), which catalyzes the conversion of arginine to nitric oxide (NO) to defend against invading pathogens (58, 59). Concurrently, NO enters vascular smooth muscle cells and binds to soluble guanylyl cyclase (sGC), activating it and promoting the production of cyclic guanosine monophosphate (cGMP) (60). As a second messenger, cGMP activates cGMP-dependent protein kinase G (PKG). PKG then phosphorylates downstream effector proteins, reducing the intracellular concentration of free Ca²⁺. This, in turn, inhibits vascular smooth muscle cell proliferation and induces their relaxation, leading to local vasodilation and an increased blood flow (61, 62). This may be associated with the clinical manifestation of facial erythema in patients with rosacea. Additionally, vasodilatation and increased permeability of newly formed capillaries lead to plasma extravasation, forming local redness and swelling, while facilitating the infiltration of more inflammatory cells and mediators into the lesion site, exacerbating local inflammation. In summary, in rosacea, angiogenesis and inflammatory responses regulate and promote each other, jointly driving disease progression.

Oxidative stress represents a pathological state of imbalance between oxidation and antioxidant defenses within the organism, leading to the excessive production of reactive oxygen species (ROS) (63). ROS are oxygen-derived reactive molecules with unpaired electrons that can induce cellular stress and damage (64, 65). Demir et al. (66) found that the thiol-disulfide homeostasis (TDH) in the serum of patients with rosacea shifts towards disulfides, indicating the presence of oxidative stress. Traditionally, neutrophils have been considered the primary source of ROS in rosacea (67–69), but recent studies suggest that macrophages may also be involved, jointly mediating oxidative stress in this disorder. Macrophages bind to bacterial lipopolysaccharide (LPS) through TLR4, prompting the Toll-IL-1R (TIR) domain of TLR4 to interact with the carboxyl terminus of the intracellular nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. This interaction catalyzes the transfer of electrons from NADPH to O₂, leading to the generation of O₂ ^-. O₂ ^- serves as a common precursor for all ROS subspecies generated within cells. It rapidly undergoes dismutation to form hydrogen peroxide (H₂O₂), which subsequently reacts to generate additional ROS, contributing to the elimination of pathogens (70, 71). Simultaneously, ROS acts as a second messenger to activate downstream mitogen-activated protein kinase (MAPK) and NF-κB signaling pathways, further regulating cytokine expression and amplifying the immune response (72, 73). Additionally, macrophage-derived TNF-α induces the production of mitochondrial ROS through TNF receptor 1 (TNFR1), which in turn inhibits the phosphatase activity of c-Jun N-terminal kinase (JNK), leading to sustained activation of the JNK pathway and promoting cell apoptosis and necrosis (74, 75).

However, excessive ROS can damage various skin cells, including keratinocytes, fibroblasts, and endothelial cells, prompting the release of pro-inflammatory cytokines such as IL-1 and TNF-α, and causing oxidative damage to the extracellular matrix (31, 76, 77), thereby disrupting skin barrier function. Additionally, ROS accumulate within macrophages, forming advanced oxidation protein products (AOPP), which leads to protein peroxidation and subsequently affects the normal structure and function of cells (78, 79). Furthermore, ROS can combine with NO catalyzed by iNOS to form peroxynitrite (ONOO^-), which damages DNA through oxidative deamination, resulting in impaired macrophage function (58, 80). Based on this, we speculate that when macrophages are damaged or die due to oxidative stress, they may release more inflammatory cytokines, further exacerbating the inflammatory response. This hypothesis needs to be validated through experimental research ( Table 1 ).

Recent studies have indicated that patients with rosacea often exhibit metabolic dysfunction and may even coexist with metabolic diseases such as obesity, hypertension, and hypercholesterolemia (81–83). Metabolic abnormalities in rosacea have gradually become a research focus, and macrophages potentially play a role in this process. M1 macrophages dominate the inflammatory response and undergo metabolic reprogramming, shifting their glucose metabolism from oxidative phosphorylation to glycolysis, which facilitates the rapid cellular response to local infection or inflammation (84, 85). However, the blockade of the tricarboxylic acid cycle leads to the accumulation of intermediate metabolites such as citrate and succinate. Citrate can induce macrophages to produce inflammatory mediators such as NO, ROS, and PG, whereas succinate stabilizes hypoxia-inducible factor-1α(HIF-1α) by inhibiting prolyl hydroxylase domain (PHD) enzymes, thereby promoting the transcription of IL-1β (86, 87). Collectively, these effects synergistically enhance the inflammatory response. As mentioned earlier, arginine in M1 macrophages is catalyzed by iNOS to produce NO and citrulline. NO not only dilates blood vessels but also, when combined with ROS to form reactive nitrogen species, can inactivate the mitochondrial electron transport chain, thereby preventing the repolarization of M1 to M2 (88, 89). This mechanism may explain the chronic and relapsing nature of rosacea, which is often difficult to cure.

However, the specific mechanisms underlying the role of macrophages in metabolic abnormalities associated with rosacea remain unclear. Tang et al. (90) found in their study using an in vitro acne disease model that M1 macrophages can promote lipid synthesis in sebocytes, significantly increasing sebum accumulation. Current research on sebaceous gland metabolism in rosacea has shown a decrease in the levels of long-chain saturated fatty acids in sebum, with no change in the total amount of sebum secreted (91). This suggests that the regulatory mechanisms of macrophages in sebaceous gland metabolism in rosacea differ from those in acne. Further research is needed to uncover the underlying mechanisms of their potential roles.

In the advanced stages of PHR, skin fibrosis occurs, during which M1 macrophages secrete matrix metalloproteinases (MMP) to degrade the extracellular matrix (ECM) (92). This process aids in the removal of damaged or necrotic tissues and creates space for the influx of new cells and the deposition of provisional ECM, thereby initiating ECM remodeling (93, 94). Additionally, M1 macrophages promote the proliferation and activation of fibroblasts through IL-1β, upregulating the expression of type I and III collagens, as well as fibronectin, leading to excessive ECM deposition and fibrosis (95). Correspondingly, activated fibroblasts release macrophage colony-stimulating factor 1 (CSF1), CCL2, and IL-6, which recruit and activate monocytes and macrophages (96, 97). Furthermore, IL-6, secreted by M1 macrophages, acts on fibroblasts to further promote fibrosis (98). However, previous studies have demonstrated that M2 macrophages play a pivotal role in fibrosis. M2 macrophages facilitate ECM deposition and remodeling by producing ECM components such as fibronectin and collagen (99). They also stimulate fibroblasts to generate a series of ECM proteins through the release of cytokines, including platelet-derived growth factor (PDGF) and TGF-β (100, 101). Additionally, M2 macrophages contribute to tissue fibrosis by modulating the activity of ECM-remodeling enzymes (102, 103). However, the mechanism of action of M2 macrophages in fibrotic lesions is more complex. In the fibrosis of organs such as the liver, kidneys, and lungs, an increased proportion of M2 macrophages, which is positively correlated with the degree of fibrosis, has been observed, along with functional dysregulation (104–106). For instance, in renal fibrosis, M2 macrophages undergo proliferation-dependent phenotypic switching induced by the overexpression of CSF1 in renal tubular epithelial cells, resulting in a functional transition from anti-inflammatory repair to profibrotic activity (107). Shen et al. (108) demonstrated that M2 macrophages secrete excessive TGF-β1, serving as the primary source of TGF-β1 in renal fibrosis, directly inducing epithelial-mesenchymal transition (EMT) in renal tubular epithelial cells. Additionally, under continuous stimulation by excessive TGF-β1, M2 macrophages undergo macrophage-to-myofibroblast transition (MMT) via the TGF-β1/Smad3 signaling pathway, secreting large amounts of collagen and thereby leading to ECM accumulation and exacerbating fibrosis progression (109, 110). Lv et al. (111) revealed that the number of M2 macrophages in the skin lesions of patients with keloids is higher than that in normal skin, with an elevated M2/M1 ratio. Moreover, during keloid formation, M2 macrophages exhibit profibrotic functions, continuously secreting TGF-β1, which activates the Smad2/3 signaling pathway in fibroblasts, induces collagen synthesis and the expression of MMP inhibitors, and creates an irreversible fibrotic microenvironment (112, 113). We hypothesize that M2 macrophages may be involved in the fibrosis observed in the late stages of PHR. However, no studies have yet demonstrated whether there are differences in the expression of M2 macrophages between rosacea and normal skin, or whether there is functional dysregulation of M2 macrophages. Further research is needed to verify these aspects in the future.