TREM2hi macrophage as a SICM therapy: road ahead is long but worthy

Dr. Fang’s group identify a unique population of CD163+Retnla+TREM2hi cardiac resident macrophages that could be a potential therapeutic strategy for SICM.
TREM2hi macrophage as a SICM therapy: road ahead is long but worthy
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Sepsis is a life-threatening organ dysfunction driven by a dysregulated host response, which affects approximately 50 million individuals and causes over 11 million fatalities worldwide annually[1,2]. Sepsis can be induced by pathogen- associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs)[3]. Heart, one of multiple organs affected by sepsis, has high energy and oxygen consumption. Sepsis-induced cardiomyopathy (SICM) is a common and important cause of death in patients with sepsis. Patients usually display the reduced ejection fraction, abnormal ventricular dilatation, poor response to fluid therapy and cardiovascular active agents[4].Of note, patients with SICM have a transient and significant improvement in cardiac function[5], suggesting that cardiac homeostasis can be restored after the septic stress[6-8]. However, the underlying mechanisms facilitating the heart rehabilitation during sepsis have not been fully elucidated, which reduces the survival of patients with SICM. Therefore, it assuredly need intensive studies to unveil the blind spots of pathogenesis and provide novel idea for the clinical treatment of SCIM.

 which is immune cell subset critical for SICM?

Cardiac immune cells are key regulator of heart microenvironment and closely related to cardiac homeostasis and diseases. So, two questions are coming up to our mind: how do cardiac immune cells change in SCIM? and which is the SCIM-associated essential cell subset? To address these questions, using flow cytometry and single cell RNA-sequencing (scRNA-seq), we analyzed 29537 cardiac immune cells from hearts of 14 wild-type (WT) mice at steady state (SS), and 3, 7 and 21 days post-CLP, respectively (PMID:36635449, DOI:10.1038/s42255-022-00715-5). We observed that macrophages were the most abundant immune cells in both WT and septic hearts, and display a dynamic change following sepsis. Intriguingly, one macrophage subset (Mac1) reduced first and recovered later on following sepsis. Mac1 subset is characterized by the expression of Trem2, Retnla, Lyve1, Cd163 and Folr2, and  resembled the transcriptomic signatures of cardiac tissue-resident macrophages. The finding that Mac1 subset associating with the recovery of cardiac function in sepsis prompts us to explore whether Mac1 is the Angels or the Demons in SICM.

 Which gene is the key regulator of SICM-associated macrophage (Mac1)?

Our RNA-seq data analysis revealed that genes upregulated in Mac1 were related with phagocytosis and endocytosis in biological terms, including the triggering receptor expressed on myeloid cells 2 (Trem2). Trem2, which is mainly expressed on the surface of macrophages, regulates the function of macrophages, and involves in pathogen phagocytosis, anti-inflammatory mediators’ production, lipid and energy metabolism10-13. Importantly, we observed Trem2 is highly expressed in Mac1 cells and essential for Mac1 remodeling during SICM. The proportion of Mac1 cells both significantly decreases in WT and Trem2-/- mice 3 days post-CLP. 7 days post CLP, Mac1 cells recovers to normal level in WT mice, but Trem2-/- mice could not restore the proportion of Mac1 cells, suggesting a key role of Trem2 in Mac1 cells. We further showed that Trem2 deficiency impairs the proliferative capability of Mac1 cells.

 What’s the function of TREM2hi Mac1?

Our fate mapping data strongly support that Mac1 cells are self-renewing resident macrophages. Nicola´s-A´ vila et al. has implied that cardiac resident macrophages could engulf a type of extracellular particles (known as exophers) which contain defective mitochondria, and preserve mitochondrial function in the heart[9]. We wonder whether TREM2hi Mac1 could protect heart function in sepsis. To address it, we constructed αMHCCre:Rosa26TdTom mouse line to track cardiomyocyte-derived exophers, as well as αMHCCre:mtD2Flox/Flox mouse line and AAV-Tnnt2-mtKeima to track cardiomyocyte-derived mitochondria. 3D reconstruction and video showed that TREM2hi Mac1 scavenged exophers and defective mitochondria released from cardiomyocytes. Furthermore, Trem2 deficiency leads to the failure of removal these defective mitochondria and consequently accelerates heart injury.

 How to understand the value of SCIM-associated macrophage subset?

We illustrate immune cells of heart under steady state, sepsis progression and recovery using single cell RNA-seq and reveal a subset of macrophage are positively related to cardiac function. We then show that the high expression of TREM2 is the key feature of these SCIM-associated macrophages and clarify their roles in septic heart. In addition, the transplantation of Mac1 subset can ameliorate the cardiac dysfunction.

Investigating the SCIM-associated macrophage subset can not only help to better understand the pathogenesis of septic heart, but also accelerate the transformation of macrophage immunotherapy. Identification of the specific markers and function of disease-associated macrophage will provide the direction of cell therapy, including designing the specific cell-killer CAR-T or transplantation of functional cells. The methods of manipulating macrophage subsets both of tissue resident macrophages or monocyte-derived macrophages in vivo and in vitro reveals the origins and plasticity of macrophage. iPSCs derived specific macrophage subsets could play important roles in popularizing macrophage immunotherapy in sepsis. Medicines targeting macrophage activity to destroy/enhance their function are relied on detailed characterization of macrophage subsets[10]. Although there is a long way to go, it’s worthy to overcome these impediments to realize it in sepsis precise treatment.

 In summary, we find TREM2hi Mac1 removes exophers released from myocardium to maintain homeostasis of septic heart and improves the outcome of SICM murine model. Our study lightens the future way in application of cellular targeted therapy including SICM-associated Mac1 subpopulations.

Author: Shiyu Chen, Hui Ye, Kai Zhang and Xiangming Fang; Photoed by Dr. Liqi Shu, Brown University; Email to xmfang@zju.edu.cn

 References

  1. Rudd, K.E., et al., Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study. Lancet (London, England), 2020. 395(10219): p. 200-211.
  2. Singer, M., et al., The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA, 2016. 315(8): p. 801-810.
  3. Singer M, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 315, 801-810 (2016).
  4. Hollenberg SM and Singer M Pathophysiology of sepsis-induced cardiomyopathy. Nature reviews. Cardiology 18, 424-434 (2021).
  5. Bréchot N, et al. Venoarterial extracorporeal membrane oxygenation to rescue sepsis-induced cardiogenic shock: a retrospective, multicentre, international cohort study. Lancet (London, England) 396, 545-552 (2020).
  6. Hulsmans M, et al. Macrophages Facilitate Electrical Conduction in the Heart. Cell 169, 510-522 e20 (2017).
  7. Lavine KJ, et al. The Macrophage in Cardiac Homeostasis and Disease: JACC Macrophage in CVD Series (Part 4). Journal of the American College of Cardiology 72, 2213-2230 (2018).
  8. Swirski FK and Nahrendorf M Cardioimmunology: the immune system in cardiac homeostasis and disease. Nature reviews. Immunology 18, 733-744 (2018).
  9. Nicolás-Ávila JA, et al. A Network of Macrophages Supports Mitochondrial Homeostasis in the Heart. Cell 183, 94-109 (2020).
  10. Sly LM and McKay DM Macrophage immunotherapy: overcoming impediments to realize promise. Trends Immunol 43, 959–968 (2022).

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