Patients with severe COVID-19 develop acute respiratory distress syndrome (ARDS) that may progress to cytokine storm syndrome, organ dysfunction, and death. Considering that complement component 5a (C5a), through its cellular receptor C5aR1, has potent proinflammatory actions and plays immunopathological roles in inflammatory diseases, we investigated whether the C5a/C5aR1 pathway could be involved in COVID-19 pathophysiology. C5a/C5aR1 signaling increased locally in the lung, especially in neutrophils of critically ill patients with COVID-19 compared with patients with influenza infection, as well as in the lung tissue of K18-hACE2 Tg mice (Tg mice) infected with SARS-CoV-2. Genetic and pharmacological inhibition of C5aR1 signaling ameliorated lung immunopathology in Tg-infected mice. Mechanistically, we found that C5aR1 signaling drives neutrophil extracellular traps-dependent (NETs-dependent) immunopathology. These data confirm the immunopathological role of C5a/C5aR1 signaling in COVID-19 and indicate that antagonists of C5aR1 could be useful for COVID-19 treatment.

Cytotoxic agents synergize with immune checkpoint inhibitors and improve outcomes for patients with several cancer types. Nonetheless, a parallel increase in the incidence of dose-limiting side effects, such as peripheral neuropathy, is often observed. Here, we investigated the role of the programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis in the modulation of paclitaxel-induced neuropathic pain. We found that human and mouse neural tissues, including the dorsal root ganglion (DRG), expressed basal levels of PD-1 and PD-L1. During the development of paclitaxel-induced neuropathy, an increase in PD-L1 expression was observed in macrophages from the DRG. This effect depended on Toll-like receptor 4 activation by paclitaxel. Furthermore, PD-L1 inhibited pain behavior triggered by paclitaxel or formalin in mice, suggesting that PD-1/PD-L1 signaling attenuates peripheral neuropathy development. Consistent with this, we observed that the combined use of anti–PD-L1 plus paclitaxel increased mechanical allodynia and chronic neuropathy development induced by single agents. This effect was associated with higher expression of inflammatory markers (Tnf, Il6, and Cx3cr1) in peripheral nervous tissue. Together, these results suggest that PD-1/PD-L1 inhibitors enhance paclitaxel-induced neuropathic pain by suppressing PD-1/PD-L1 antinociceptive signaling.

Psoriasis is a chronic inflammatory skin disorder characterized by aberrant keratinocyte proliferation and immune cell infiltration with upregulation of inflammatory cytokines. Here, we examined the contribution of HCAR2 encoding for the short-chain fatty acid receptor GPR109A. Human and mouse RNA sequencing public datasets reveal elevated HCAR2 gene expression in psoriatic as compared with healthy skin, both in keratinocytes and myeloid cells. Immunostaining and flow cytometry of imiquimod-induced psoriatic-like lesions in Hcar2-mRFP reporter mice showed increased GPR109A expression by keratinocytes and inflammatory cells. GPR109A-deficient mice demonstrated a more severe imiquimod-induced psoriasis-like response than wild-type mice, with exacerbated epidermal hyperplasia, dermal inflammatory cell infiltration, and increased inflammatory mediators myeloperoxidase, CXCL5, LCN2, interleukin (IL)-1β, IL-6, IL-23, and IL-17A. Conversely, topical administration of sodium butyrate reduced imiquimod-induced skin inflammation in wild-type mice, but not in GPR109A-deficient mice. Mechanistically, GPR109A agonist butyrate inhibits histone deacetylase 3, thus inhibiting IL-1β and the inflammatory IL-1β/IL-23/IL-17A axis in imiquimod-induced skin inflammation. Therefore, GPR109A may have a protective role in psoriasis pathogenesis, supporting a potential therapeutic benefit of sodium butyrate administration or other GPR109A agonists for treating psoriasis.

SUMMARY: Macrophages play integral roles in maintaining homeostasis and function in their tissues of residence. In the skin, prenatally seeded and highly specialized macrophages physically interact with sensory nerves and contribute to their regeneration after injury. However, mechanisms underlying the development and maintenance of this potentially lifelong commitment of macrophages to nociceptors remain largely elusive. Here, we found that infiltrating myeloid progenitor cells approached the sprouting axons of sensory nerves and gradually adopted a nerve-associated macrophage-like profile. This change in identity was steered and maintained by the immediate microenvironment, in particular TGF-β, which was locally activated by the physical interaction with nerves and integrin-mediated cleavage. Following injury, TGF-β driven specification of macrophages essentially supported nerve regeneration. Overall, we identified TGF-β as a central mediator governing local imprinting and long-term specialization of macrophages in the skin, providing insights into the bidirectional communication between macrophages and sensory nerves.