Response to Letter Regarding Article “Retention of the NLRP3 Inflammasome-Primed Neutrophils in the Bone Marrow Is Essential for Myocardial Infarction-Induced Granulopoiesis”

Response:

We thank Ren et al for their interesting observations on the conflicting roles of S100A8/A9 in the inflammatory continuum during myocardial infarction (MI). However, we would like to emphasize that this particular study was focused mainly on defining the signaling pathways that sustain granulopoiesis rather than how it is regulated after initiation. Having said that, we do agree that S100 family proteins have variety of functions based on post-translational modifications, oligomeric states, availability of binding partners and even expression levels¹. This flexibility and multiplicity of functions is also reflected in its disparate roles in initiation/ resolution of inflammation. For example, lower concentrations of S100B can promote macrophage polarization towards reparative M2 phenotype while higher concentrations impair this process². Similarly, short-term pharmacological inhibition of S100A8/A9 reduce inflammation and myocardial damage³ while global/ long-term inhibition leads to deterioration of cardiac function after MI^{4, 5}. These conflicting observations point to a paradigm where S100A8/A9 has dual roles, i.e., initiation of inflammation and its subsequent resolution.

The cellular landscape and the temporally-regulated immune cell infiltration to the heart post-MI may offer some clues regarding the seemingly opposite functions of S100A8/A9. As reported previously by us and others, neutrophils dominate the initial swarming of the ischemic heart, followed by the pro-inflammatory Ly6C^hi and anti-inflammatory ly6C^lo monocyte subsets⁴. Given that S100A8/A9 are predominantly neutrophil-derived and released in excess amounts locally within the heart, it is conceivable the earliest response is a manifestation of the interaction between S100A8/A9 and the predominant cell type, i.e., neutrophils, leading to priming of the NLRP3 inflammasome. As the time progresses, the Ly6C^hi monocytes start accumulating and, thus S100A8/A9 may engage Ly6C^hi cells (i.e., predominant) differently to initiate maturation towards a reparative phenotype⁵. This is perhaps the reason why short-term inhibition of S100A8/A9 improved cardiac function, while long-term suppression beyond the pro-inflammatory phase or global deletion of S100A8/A9 impaired Ly6C^hi monocyte reprogramming leading to inadequate myocardial repair.

Ren et al rightly points out the importance of understanding of the dual functions of S100A8/A9. This understanding should allow us to better discern when and how much inflammation to target caused by MI. This should enable us to demarcate the time window for therapeutic intervention to maintain the homeostatic functions of inflammation while also preventing excessive collateral damage. This should also allow us to titrate inflammation into an ideal goldilocks zone between “not too little” and “not too much” to prevent adverse remodeling and descent into heart failure.