Autophagy enhances NFκB activity in specific tissue macrophages by sequestering A20 to boost antifungal immunity.

Immune responses must be well restrained in a steady state to avoid excessive inflammation. However, such restraints are quickly removed to exert antimicrobial responses. Here we report a role of autophagy in an early host antifungal response by enhancing NFκB activity through A20 sequestration. Enhancement of NFκB activation is achieved by autophagic depletion of A20, an NFκB inhibitor, in F4/80(hi) macrophages in the spleen, peritoneum and kidney. We show that p62, an autophagic adaptor protein, captures A20 to sequester it in the autophagosome. This allows the macrophages to release chemokines to recruit neutrophils. Indeed, mice lacking autophagy in myeloid cells show higher susceptibility to Candida albicans infection due to impairment in neutrophil recruitment. Thus, at least in the specific aforementioned tissues, autophagy appears to break A20-dependent suppression in F4/80(hi) macrophages, which express abundant A20 and contribute to the initiation of efficient innate immune responses

Obesity-induced changes in T-cell metabolism are associated with impaired memory T-cell response to influenza and are not reversed with weight loss

Background: Obesity is an independent risk factor for increased influenza mortality and is associated with impaired memory T-cell response, resulting in increased risk of infection. In this study, we investigated if weight loss would restore memory T-cell response to influenza. Methods: Male C57BL/6J mice were fed either low-fat or high-fat diet to induce obesity. Once obesity was established, all mice received primary infection with influenza X-31. Following a recovery period, we switched half of the obese group to a low-fat diet to induce weight loss. Fifteen weeks after diet switch, all mice were given a secondary infection with influenza PR8, and memory T-cell function and T-cell metabolism were measured. Results: Following secondary influenza infection, memory T-cell subsets in the lungs of obese mice were decreased compared to lean mice. At the same time, T cells from obese mice were found to have altered cellular metabolism, largely characterized by an increase in oxygen consumption. Neither impaired memory T-cell response nor altered T-cell metabolism was reversed with weight loss. Conclusion: Obesity-associated changes in T-cell metabolism are associated with impaired T-cell response to influenza, and are not reversed with weight loss