CX3CR1 Deficiency Attenuates DNFB-Induced Contact Hypersensitivity through Skewed Polarization towards M2 Phenotype in Macrophages

Abstract

CX3CL1 can function as both an adhesion molecule and a chemokine for CX3CR1+ cells, such as T cells, monocytes, and NK cells. Recent studies have demonstrated that CX3CL1–CX3CR1 interaction is associated with the development of various inflammatory skin diseases. In this study, we examined CX3CR1 involvement in 2,4-dinitrofluorobenzene (DNFB)-induced contact hypersensitivity using CX3CR1−/− mice. Ear swelling and dermal edema were attenuated after DNFB challenge in CX3CR1−/− mice. Expression of TNF-α, IL-6, and M1 macrophage markers was decreased in the ears of CX3CR1−/− mice, whereas expression of M2 macrophage markers including arginase-1 was increased. Decreased TNF-α and IL-6 expression and increased arginase-1 expression were found in peritoneal macrophages from CX3CR1−/− mice. Furthermore, ear swelling was attenuated by depleting dermal macrophages in wild-type mice to a similar level to CX3CR1−/− mice. These results suggest that CX3CR1 deficiency could induce skewed polarization towards M2 phenotype in macrophages, resulting in attenuation of contact hypersensitivity response.

Immune Metabolism–An Opportunity to Better Understand Allergic Pathology and Improve Treatment of Allergic Diseases?

“…Besides, M1 pro-inflammatory macrophages (glycolytic phenotype) ( 122 , 123 ) are also involved in asthma reactions. Interestingly, a study in a mouse model of 2,4-dinitrofluorobenzene-induced contact hypersensitivity demonstrated that M2 macrophages protected from local Th2 responses ( 124 ). These findings demonstrated that APCs might show different metabolic phenotypes in different allergic responses and further affect allergic reactions.…”

Macrophages and fibroblasts underpin skin immune responses

“…For example, arginase-1 deficiency in lysozyme M (LysM) + cells including monocytes and macrophages resulted in exacerbation of CHS through upregulated inducible nitric oxide synthase (iNOS) expression [20]. Consistently, we recently reported that CHS in CX3C chemokine receptor 1 (CX3CR1)-deficient mice was attenuated with increased expression of arginase-1, which is a representative M2 macrophage marker [21]. Furthermore, dermal macrophage depletion in wild type (WT) mice before elicitation phase suppressed CHS, suggesting important roles of macrophages in CHS.…”

Multiple roles of macrophage in skin

“…In general, M2 macrophages suppress Th1 responses, and skewed polarization towards M2 of macrophages in the lesion of contact dermatitis attenuates the inflammation [14]. CXCR1 deficiency reduces the expression of markers of M1 macrophage in the mouse models of contact dermatitis [15]. However, other mouse studies suggested the importance of M2 macrophages in the pathogenesis of contact dermatitis.…”