Mkp-1 deficiency strengthens immune defense against fungal infection

Abstract Fungal infections are a serious threat to people with a compromised immune system. The initiation of an immune response toward fungal pathogens relies on the recognition of fungal molecular patterns through pathways mediated by TLRs and C-type lectin receptors. Activation of these pathways converges on both NF-κB and MAPKs to initiate cytokine and chemokine production, leading to recruitment of inflammatory/phagocytic leukocytes and pathogen elimination. Mkp-1 is a negative regulator of the innate inflammatory response triggered by pathogen recognition, acting to attenuating cytokine production by deactivating p38 and JNK. To understand the role of Mkp-1 in immune defense against fungal pathogens, we assessed the effects of Mkp-1 deficiency on the immune response to C. albicans, the most common fungal pathogen. Contrary to our previous observation with bacterial pathogens such as E. coli or bacterial products such as LPS, Mkp1−/− mice were protected from infection with a lethal dose of C. albicans, which correlates with lower kidney fungal burdens. In response to C. albicans challenge, Mkp1−/− mice produced greater TNF-α. Interestingly, in response to heat-killed C. albicans yeasts and hyphae Mkp-1−/− macrophages also produced significantly greater amounts of TNF-α and had markedly higher p38 and JNK activities than did wildtype macrophages. TNF-α production in both wildtype and Mkp1−/− macrophages in response to heat-killed C. albicans (both yeast and hypha forms) was attenuated by the specific inhibitors of MEK1, JNK, and p38 as well as Syk. Taken together, our results suggest that during fungal infection Mkp-1 acts to restrain the production of cytokines and thus hamper the immune response against fungal infections.