An Anti-Inflammatory Role for NLRP10 in Murine Cutaneous Leishmaniasis

Abstract

The role of the nucleotide-binding domain and leucine-rich repeat containing receptor NLRP10 in disease is incompletely understood. Using three separate mouse strains lacking the gene encoding NLRP10, only one of which had a coincidental mutation in DOCK8, we documented a role for NLRP10 as a suppressor of the cutaneous inflammatory response to Leishmania major infection. There was no evidence the enhanced local inflammation was due to enhanced inflammasome activity. NLRP10/DOCK8 dually deficient mice harbored lower parasite burdens at the cutaneous site of inoculation than wild-type controls, whereas singly NLRP10 deficient had similar parasites loads to controls, suggesting that DOCK8 promotes local growth of parasites in the skin whereas NLRP10 does not. NLRP10-deficient mice developed vigorous adaptive immune responses, indicating there was not a global defect in development of antigen specific cytokine production. Bone marrow chimeras showed the anti-inflammatory role of NLRP10 was mediated by NLRP10 expressed in resident cells in the skin, rather than bone marrow-derived cells. These data suggest a novel role for NLRP10 in the resolution of local inflammatory responses during L. major infection.

Local Skin Inflammation in Cutaneous Leishmaniasis as a Source of Variable Pharmacokinetics and Therapeutic Efficacy of Liposomal Amphotericin B

“…The leakiness of the dermal capillaries, swelling/edema in the skin tissue (indicated by lesion size), and numbers of infiltrating macrophages or other inflammatory cells were higher in L. major than in L. mexicana CL at all stages of disease. These findings are consistent with earlier reports ( 45 – 47 ). Moreover, the HL and PL observations support this inflammation-driven theory of enhanced drug accumulation.…”

NLRP10 Affects the Stability of Abin-1 To Control Inflammatory Responses

“…However, Krishnaswamy et al (44) did not find any effect of NLRP10 on the inflammasome activation in macrophages and dendritic cells of NLRP10 knockout mice. Recent studies showed a role of NLRP10 in the resolution of local inflammatory responses during L. major infection (19) and a positive effect of NLRP10 on the IL-12 release by dendritic cells (20). The pathways underlying these diverse functions of NLRP10 remain to be uncovered.…”

“…The physiological role of NLRP10 in inflammasome formation or activation, however, remains controversial, as Nlrp10 knockout mice have no obvious defect in NLRP3-mediated responses (17). By contrast, inflammasomeindependent pro-and anti-inflammatory roles of NLRP10 in Shigella flexneri and Leishmania major infection were also described (18,19), combined with work suggesting a role of NLRP10 in enhancing T cell responses by increasing IL-12 production by dendritic cells (20). NLRP10 is highly expressed in the epidermis of the skin, where keratinocytes express several pattern recognition receptors important for host defense against bacterial, viral, and fungal pathogens (18,(21)(22)(23).…”

Control of cell death‐associated danger signals during cornification prevents autoinflammation of the skin

“…Pyrin domain containing 1 (PYDC1), an inhibitor of inflammasomes and pro‐inflammatory signalling is massively upregulated during keratinocyte differentiation at least at the mRNA level . NOD‐like receptor family pyrin domain containing 10 (NLRP10), which lacks the leucine‐rich domain present in pro‐inflammatory NLRPs, inhibits inflammation and is predominantly expressed in terminally differentiated keratinocytes (Figure , right panel; Figure ) . Knockout of NLRP10 did not impair epidermal cornification but reduced contact hypersensitivity responses in mice .…”