M2 macrophages suppress inflammation in numerous disorders, including tumour formation, infection and obesity. However, the exact role of M2 macrophages in the context of several other diseases is still largely undefined. We here show that human M2 macrophages promote inflammation instead of suppressing inflammation on simultaneous exposure to complexed IgG (c-IgG) and TLR ligands, as occurs in the context of diseases such as rheumatoid arthritis (RA). c-IgG-TLR ligand co-stimulation of M2 macrophages selectively amplifies production of pro-inflammatory cytokines TNF-α, IL-1β and IL-6 and promotes Th17 responses, which all play a critical role in RA pathology. Induction of pro-inflammatory cytokines on c-IgG co-stimulation mainly depends on Fc gamma receptor IIa (FcγRIIa), which selectively amplifies cytokine gene transcription and induces caspase-1 activation. These data indicate that FcγR-TLR cross-talk may be targeted for treatment to attenuate inflammation in RA, by restoring the anti-inflammatory function of M2 macrophages.

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IntroductionBiomarkers complementing clinical evaluations may help to reduce the length and size of proof-of-concept (PoC) trials aimed to obtain quick “go/no go” decisions in the clinical development of new treatments. We aimed to identify and validate serum biomarkers with a high sensitivity to change upon effective treatment in spondyloarthritis (SpA) PoC trials.MethodsThe candidate biomarkers high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), pentraxin-3 (PTX-3), alpha-2-macroglobulin (alpha-2-MG), matrix metalloproteinase-3 (MMP-3), calprotectin, and vascular endothelial growth factor (VEGF) were determined by enzyme-linked immunosorbent assay (ELISA) in healthy controls (n = 20) and SpA patients before and after 2 weeks of infliximab (n = 18) or placebo (n = 19) treatment in cohort 1. Clinical outcome was evaluated at week 12. Results were validated in ankylosing spondylitis (AS) with infliximab (cohort 2, n = 21) and peripheral SpA with etanercept (cohort 3, n = 20).ResultsSerum levels of calprotectin, hs-CRP, PTX-3, VEGF (all P < 0.001) and MMP-3 (P = 0.062), but not IL-6 and alpha-2-MG, were increased in SpA versus healthy controls. Treatment with infliximab, but not placebo, significantly decreased calprotectin (P < 0.001) and hs-CRP (P < 0.001) levels, with a similar trend for MMP-3 (P = 0.063). The standardized response mean (SRM), which reflects the ability to detect changes over time, was high for calprotectin (−1.26), good for hs-CRP (−0.96) and moderate for MMP-3 (−0.52). Calprotectin and hs-CRP, but not MMP-3, were good biomarkers for treatment response in axial and peripheral SpA as evaluated and confirmed in cohort 2 and 3 respectively.ConclusionsCalprotectin and hs-CRP are good serum biomarkers with high sensitivity to change upon effective treatment at the group level in small-scale, short term PoC trials in SpA.