Monocyte exhaustion associated with systemic lupus erythematosus

Monocytes are major contributors to systemic lupus erythematosus (SLE) pathogenesis, modulating B- and T-cell autoreactivity through inflammatory cytokine secretion and disrupted immune clearance. Under prolonged inflammatory pressure, monocytes develop a pathogenic "exhausted" immune memory state defined by paradoxical proinflammatory and immunosuppressive gene expression and diminished immune effector functions. To determine whether chronic inflammation in SLE elicits a similar monocyte exhaustion phenotype, we analyzed bone marrow and splenic reservoir monocytes from lupus-prone MRL and MRL/lpr (LPR) mice. Monocytes from LPR mice exhibit chronic immune exhaustion, including reduced chemokine receptor CX3CR1 cell surface levels, heightened sensitivity to endotoxin stress, and altered expression of T cell regulatory molecules PD-L1, CD200R, ICOS-L, and CD86. Exhaustion severity correlated with SLE progression, although the development of monocyte exhaustion preceded the onset of disease symptoms. These features were largely recapitulated in monocytes from patients with SLE, demonstrating that monocyte exhaustion is a generalizable feature of SLE pathogenesis.