Hypotesis-Driven Dissection of Molecular Components of Innate Immunity and Inflammation: From Cancer to COVID-19

Inflammation is a manifestation of innate immunity and has emerged as a metanarrative of modern medicine (Mantovani et al , Immunity, 2019;Furman et al , Nature Medicine, 2019), a component of diverse disease ranging from cancer to COVID-19 (Mantovani et al , Nature 2008;Mantovani e Netea, New England Journal of Medicine, 2020 in press) Dissection of the diversity and complexity of regulatory pathways of innate immunity has taken advantage of hypothesis driven and nonhypothesis driven approaches IL-1 is the prototypic member of a complex family of cytokines and receptors which play a central role in innate immunity and in the activation and regulation of adaptive immune responses (Mantovani et al Immunity, 2019) Based on structure, we originally hypothesized that IL-1R2 should behave as a decoy receptor, a tenet confirmed by extensive experimental data In the same line, we cloned IL-1R8 and focused on it based on the hypothesis that it would behave as a negative regulator IL1R8 was then found to be a negative regulator of signaling downstream of members of the IL-1 and Toll like receptor (TLR) family and a component of the receptor complex recognized by the anti-inflammatory immunosuppression cytokine IL-37 As a result of a fishing expedition we originally cloned PTX3 as a gene induced by IL-1 (Garlanda et al , Physiol Rev, 2020) This distant relative of C reactive protein (CRP) was then found to represent an essential component of the humoral of innate immunity playing a role in antimicrobial resistance and in the regulation of inflammation The latter includes selected solid tumors and hematological malignancies (Garlanda et al , Physiol Rev, 2020) We also cloned in silico PTX4, but its function remains to be defined Interestingly, PTX3 was recently found to be highly expressed in monocytes and lung macrophages at population and single cell level in COVID-19 and to represent a candidate novel biomarker of disease severity (Brunetta et al , medRxiv, 2020) Stemming from our interest in macrophage diversity and polarization (Locati, Curtale, Mantovani, Ann Rev Pathol 2020;Mantovani et al , Nature Rev Clin Onc 2017;Jaillon et al , Nature Rev Cancer 2020) We identified the tetraspan MS4A4A, a gene of unknown function, as a gene associated with M2-like macrophage polarization (Mattiola et al , Nat Immunol 2019) We found that MS4A4A partner with Dectin-1 and is essential for full syk signalling downstream of this pattern recognition receptors The examples discussed above, selected from our previous and ongoing research efforts, highlight the complexity of innate immunity and its regulation The dissection of the daunting complexity and diversity of cellular and human innate immunity requires the use of unbiased non-hypothesisdriven approaches complemented by hypothesis-driven, biased experimental and clinical testing