Soluble immune factors are essential elements in the defensive system of invertebrate metazoans, and include enzymes such as lysozyme and phenoloxidase, complement and inflammatory cytokines such as IL-17 and TNF (1–6). A comprehensive analysis of soluble factors-mediated immunity in two different invertebrate phyla, annelids and bivalve mollusks, is reported by an excellent group of four women scientists active in two different European countries (Canesi et al.). Two studies from Italy and Italy-China analyzed the immune response of tunicates to biotic or abiotic challenges and showed that the modulation of several immune factors, including complement, cytokines, enzymes and variable chitin-binding and LPS-binding proteins, is the basis of primary and memory responses in Ciona robusta (Marino et al., Liberti et al.).

In mammalian immunity, soluble factors have a major importance both for innate and adaptive immune response. As for invertebrates, complement is one of the key anti-bacterial effector systems (4, 7, 8). For adaptive immunity, antibodies are the highly specific and effective neutralizing tools (8). Cytokines and chemokines are soluble factors that participate to both innate and adaptive immunity, representing the natural bridge between the two systems (8). The role of soluble factors in the T cell development has been extensively examined, including at the level of intrathymic differentiation (8, 9). A very interesting study addresses the role of two such factors, IL-2 and IL-15, in driving the differentiation of distinct Treg cells in the thymus (Apert et al.). It is notable that such study is the result of a collaboration between three different European countries, France, Switzerland and UK. A comprehensive assessment of the multifaceted role of chemokines in immunity is provided by a young researcher active in one of the groups that discovered chemokines, in Switzerland (Cecchinato et al.). The ability of innate cells such as macrophages to produce cytokines and other soluble factors in response to challenges is generally assessed in vitro in culture systems that may not reproduce accurately the in vivo conditions (10, 11). This is a shortcoming that may lead to misleading results and inaccurate prediction of immune reactivities. A joint collaboration between Dutch, UK and German researchers pointed out how variations in cell density in culture can influence the function and cytokine production by human macrophages, which warrants a particular attention in the reliable design of our cell culture systems (Ruder et al.).

The role of cytokines and other immune soluble factors in diseases has gained increasing importance, and many studies have pointed at the possibility of using them as diagnostic markers, able to identify the type and stage of multiple different diseases, and as prognostic tools for predicting future susceptibility or resistance to disease development.

Whether anomalies in cytokine production is a consequence of disease or may be part of the pathogenesis is still an open question. Several studies included in this collection tackle the issue in the attempt to identify the involvement of cytokines in pathogenesis vs. pathology. Several of the studies focused on cytokines of the IL-1 family, which include highly inflammatory factors, such as IL-1β, that have a well-known role in many chronic inflammatory and degenerative diseases (12, 13). A manuscript from Italy and China examined the role of IL-1 family cytokines in neuroinflammatory and neurodegenerative diseases and concluded that most likely these cytokines are involved in both pathogenesis and downstream pathological symptoms (Boraschi et al.). That IL-1β, the best-known inflammatory cytokine of the family, can be involved in tumorigenesis is known (14, 15), but a study from Singapore and Switzerland further identified AIM2 activation as one of the factors contributing to the production of IL-1β in the tumor microenvironment (Chew et al.). IL-1α, a cytokine mostly present as membrane bound molecule thereby acting through cell-to-cell contact (16, 17), was found responsible for activating leukocyte adhesion during atherogenesis in a German study (Maeder et al.). Another German study found that IL-36γ, a less known inflammatory cytokine of the IL-1 family mostly active at the tissue level, is responsible for interferon-independent liver injury caused by the Rift Valley virus (Anzaghe et al.). Other specific cases were examined: the role of IL-11 in fibrosis in interstitial lung disease, studied using human organoids by a German group (Kastlmeier et al.); the dysregulation of LIF in endometriosis, proposed by a Canadian-USA collaboration (Zutautas et al.); the role of GAS6/TAM in regulating NK cell recognition of multiple myeloma cells and degranulation studied by an Italian-USA group (Kosta et al.); and the involvement of the complement terminal complex in the inflammatory activation of retinal pigment epithelium and the associated development of age-related macular degeneration proposed by a German collaboration study (Busch et al.). Eventually, a group of studies examined the entire spectrum of cytokines and soluble factors associated with initiation vs. maintenance of different pathologies. A collaborative study between Switzerland and Spain reviewed the contribution of cytokines to the hyperinflammatory spectrum (Planas et al.). A USA group reviewed the contribution of oncostatin M, a cytokine of the IL-6 family, in inflammatory diseases (Wolf et al.). In cancer, the contribution of tumor-associated macrophages and their soluble factors in lung metastatic melanoma was addressed in a China-Germany collaborative study (Xiong et al.). Eventually, an informative review on the role of cytokines in Acute Myeloid Leukemia was contributed by an Austrian group (Luciano et al.).

Targeting cytokines for curing diseases is an approach that has turned out to be successful in several instances, see as an example the TNF-α or IL-1β inhibitory biologicals currently used in several chronic inflammatory diseases (18–21), although the efficacy is not complete and side effects can be observed [such as the tuberculosis activation in patients with latent tuberculosis treated with anti-TNF-α drugs; (22)]. An historical excursus describing how several of these cytokine inhibitors were originally identified is provided by Daniela Novick, a pioneer woman scientist who accelerated substantially the development of anti-cytokine drugs (Novick et al.). Inflammation, including induction of inflammatory cytokines, has been for decades the core of cancer immunotherapy, with the use of bacteria and bacterial-derived molecules (23). The use of BCG is currently the golden standard treatment for non-invasive bladder cancer, and its effect includes the activation of an anti-tumor innate and inflammatory response (24, 25). Based on the notion that innate immunity is non-specific, a large collaborative study (involving researchers from Austria, The Netherlands, France, Italy, Russia, Poland and Hong Kong) showed that treatment of bladder cancer patients with BCG induced a systemic innate response able to counteract the SARS-CoV-2 infection (Pichler et al.). On the same line, a very interesting study from an Iranian and Canadian collaboration shows that the use of molecules that induce innate/inflammatory activation can substantially increase the therapeutic immune response against colon cancer in a preclinical model and also downregulates the pathological presence of fibroblasts in the tumor microenvironment (Haijabadi et al.). A review of the innate immunity in the airways, contributed by an Icelandic/Swedish group, comes to similar conclusions, i.e., that activation of innate immune/inflammatory epigenetic mechanisms by bacterial products may contribute to effective response and disease resolution (Myszor and Gudmundsson).

Anti-inflammatory strategies are the most common approaches to cytokine inhibition in different diseases. In liver transplantation from brain dead donors, inflammation is largely dependent on increased IL-1β production and was shown, in a study from a Mexico-Spain-Uruguay collaboration, to be the main cause of rejection, as it could be mitigated by treatment with the IL-1 antagonist IL-1Ra (Casillas-Ramirez et al.). Interestingly, a German-UK study on IL-37, an anti-inflammatory cytokine of the IL-1 family that is active in the gut, showed that the IL-37 role at the level of the mucosal epithelium is minimal, suggesting an anatomically distinct and localized anti-inflammatory activity (Krohn et al.). Among anti-inflammatory strategies, the use of phycocyanobilin, a tetrapyrrole chromophore from microalgae, displays substantial anti-inflammatory properties and was found able to inhibit leukocyte infiltration and cytokine production in a rheumatoid arthritis model (Marin-Prida et al.) and in a multiple sclerosis model (Marin-Prida et al.), as reported by two Cuban studies, one in collaboration with Brazil, China, Mexico, and the other one with Brazil and Germany. A French study explored the use of a synthetic histamine analogue that binds to CXCR4 (a chemokine receptor important for leukocyte mobilization) for inhibiting inflammation in juvenile arthritis cells in vitro and in a mouse model in vivo. Using this model, they observed substantial reduction of inflammatory cytokines, immune cell infiltration and joint and bone erosion (Bekaddour et al.). Anti-inflammatory effects were also observed in a Cuban study using a modified peptide derived from HSP60 both in animal models of RA and in human patients The treatment inhibited inflammatory cytokine production, including IL-17, and ameliorated the cytokine storm in COVID-19 patients (Dominguez-Horta et al.). Anti-inflammatory strategies targeting T cells included the above-mentioned study, which identified an increase in Treg cells, and a collaborative study between Cuba, Korea and Portugal on a mutant of IL-2, which showed that the antitumor activity of the mutein is based on the change of the balance between CD8⁺ and Treg cells (Carmenate et al.). Eventually, an Italian study showed that a synthetic sulfolipid can decrease IL-12 production by dendritic cells and promote T cell differentiation towards Treg (Barra et al.).