The C3–C3aR axis modulates trained immunity in alveolar macrophages

The immune protein C3 plays a key role in mucosal immune responses, including combating microbes and boosting inflammation. Trained immunity, or the heightened secondary reactions of innate immune cells after initial exposure, is an area of study. The impact of complement proteins on trained immune responses, however, is not well understood. Researchers examined the involvement of C3 in trained immunity, specifically focusing on alveolar macrophages (AMs), a type of immune cell present in the lungs.

Following intranasal exposure to a training stimulus, the levels of C3 and its receptor, C3aR1, in AMs were observed to rise in humans. In mice, trained immune systems exhibited increased proinflammatory cytokines and higher levels of C3a upon a second stimulus. In the absence of C3, trained AMs showed decreased production of chemokines and cytokines, as well as reduced phagocytosis and reactive oxygen species production compared to wild-type AMs.

Confocal microscopy of live mouse alveoli revealed that AMs rapidly engulfed C3 after exposure, unlike C3a. Restoring the blunted cytokine output was achieved by introducing exogenous C3, but not by C3a alone.

The presence of C3aR, the receptor for C3a, was crucial for this restoration. Inhibiting C3aR, both with pharmacological means and through genetic knockout, prevented the recovery of cytokine output, indicating the necessity of C3aR engagement. Additionally, trained wild-type AMs exhibited enhanced glycolytic activity, a characteristic that was rectified by exogenous C3 in a C3aR-dependent manner.

These findings demonstrate that C3 regulates trained immunity in AMs through C3aR signaling, shedding light on a previously unexplored role for C3 in this process.