Cigarette smoke acts via c-Src to decrease CXCL11 levels and deter lung Treg responses in HIV-related COPD

Background: Inflammation drives COPD in people living with HIV, and the HIV virus impairs T regulatory (Treg) cell responses that deter immune-mediated lung injury. Aims: We determined how cigarette smoke exposure alters lung Treg responses to increase the susceptibility to COPD in people living with HIV. Methods: Lung lavage levels of the Treg chemoattractant CXCL11 were quantified in a cohort of 26 HIV-infected subjects and 42 age-matched controls.  To ascertain how CXCL11 modifies lung Treg responses, analyses were conducted using a chimeric HIV (EcoHIV) infection smoke exposure mouse model and elastase treatment of Treg depleted (DEREG) mice. Results: CXCL11 lung lavage levels increased in HIV+ subjects compared to controls. However, CXCL11 levels were significantly lower in those HIV+ subjects with a reduced diffusing capacity for carbon monoxide compared to HIV+ subjects with normal lung function. Cigarette smoke exposure reduced CXCL11 levels in human subjects and decreased lung Cxcl11 levels and Treg frequency in control and EcoHIV-infected mice. Cigarette smoke increased lung c-Src activity in mice and the c-Src inhibitor AZD0530 restored Cxcl11 expression in smoke exposed mice and alveolar macrophages. Direct administration of CXCL11 protein to the airways of EcoHIV infected or smoke exposed mice significantly enhanced lung Treg responses. Treg deficient DEREG mice exhibited increased airway resistance at baseline and had greater lung tissue destruction post elastase treatment. Conclusions: Cigarette smoke activates c-Src to suppress CXCL11 levels thereby diminishing lung Treg responses that counter airways disease and lung tissue destruction in HIV+ individuals.