By Binding SIRPα or Calreticulin/CD91, Lung Collectins Act as Dual Function Surveillance Molecules to Suppress or Enhance Inflammation

a signaling partner (Su et al., 2002). A closely related function for the collectins is recognition and removal of Denver, Colorado 80262 apoptotic cells (Ogden et al., 2001) wherein the collectin family molecules bind via their globular heads to the apoptotic cell surface and mediate ingestion through a Summary unique form of stimulated macropinocytosis induced by interaction of their collagenous tails with calreticulin/ Surfactant proteins A and D (SPA and SP-D) are lung collectins composed of two regions, a globular head CD91 (Ogden et al., 2001). In keeping with these observations , mice deficient in C1q or SP-D show defects domain that binds PAMPs and a collagenous tail domain that initiates phagocytosis. We provide evidence in apoptotic cell clearance in vivo (Botto et al., 1998; Vandivier et al., 2002). that SPA and SP-D act in a dual manner, to enhance or suppress inflammatory mediator production de-In sharp contrast to the potentially proinflammatory effects of PAMP recognition by collectins, mice deficient pending on binding orientation. SPA and SP-D bind SIRP␣ through their globular heads to initiate a signal-in SPA or SP-D exhibit-enhanced inflammatory responses in the lung to a variety of stimuli (Greene et al., ing pathway that blocks proinflammatory mediator production. In contrast, their collagenous tails stimu-2000; LeVine et al., 2000; Restrepo et al.,1999). SP-D overexpressing mice show the opposite, i.e., decreased late proinflammatory mediator production through binding to calreticulin/CD91. Together a model is im-inflammation. These observations have led to the suggestion that SPA and SP-D may exhibit anti-inflamma-plied in which SPA and SP-D help maintain a non/ anti-inflammatory lung environment by stimulating tory effects in the lung, perhaps to maintain this highly exposed organ in a quiet, noninflamed state. The appar-SIRP␣ on resident cells through their globular heads. However, interaction of these heads with PAMPs on ent paradox is maintained in conflicting reports of sur-factant protein induction (Kremlev and Phelps, 1994; foreign organisms or damaged cells and presentation of the collagenous tails in an aggregated state to cal-of inflammatory mediator production from macrophages in vitro. The potentially suppressive effects seem to be mediated by the globular Introduction head domains of the surfactant proteins (Sano et al., 1998) and lead to the hypothesis proposed herein, The collectin family of molecules are generally thought to function as components of the innate immune system, namely that it is the orientation of the SPA or SP-D and acting to protect the host by …