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Chronic infection stunts macrophage heterogeneity and disrupts immune-mediated myogenesis
Richard M. Jin, … , Jordan Warunek, Elizabeth A. Wohlfert
Richard M. Jin, … , Jordan Warunek, Elizabeth A. Wohlfert
Published September 20, 2018
Citation Information: JCI Insight. 2018;3(18):e121549. https://doi.org/10.1172/jci.insight.121549.
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Research Article Infectious disease Inflammation

Chronic infection stunts macrophage heterogeneity and disrupts immune-mediated myogenesis

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Abstract

The robust regenerative potential of skeletal muscle is imperative for the maintenance of tissue function across a host of potential insults including exercise, infection, and trauma. The highly coordinated action of multiple immune populations, especially macrophages, plays an indispensable role in guiding this reparative program. However, it remains unclear how skeletal muscle repair proceeds in a chronically inflamed setting, such as infection, where an active immune response is already engaged. To address this question, we used a cardiotoxin injury model to challenge the reparative potential of chronically infected muscle. Compared with regenerating naive skeletal muscle, infected skeletal muscle exhibited multiple indicators of delayed muscle repair including a divergent morphologic response to injury and dysregulated expression of myogenic regulatory factors. Further, using both flow cytometric and single-cell RNA sequencing approaches, we show that reduced macrophage heterogeneity due to delayed emergence of restorative subsets underlies dysfunctional tissue repair during chronic infection. Our findings highlight how the preexisting inflammatory environment within tissue alters reparative immunity and ultimately the quality of tissue regeneration.

Authors

Richard M. Jin, Jordan Warunek, Elizabeth A. Wohlfert

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Figure 1

Morphologic analysis of muscle regeneration following acute sterile injury in naive and chronically infected muscle.

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Morphologic analysis of muscle regeneration following acute sterile inju...
(A) Experimental design for CTX-induced injury during chronic T. gondii infection. (B) Representative wheat-germ agglutinin (WGA, green) and DAPI (blue) staining of naive (top) and chronically infected skeletal muscle (bottom) during CTX-induced injury at days 0 (no CTX), 1, 4, and 10 after injury. Scale bars: 100 μm. (C) Fiber size frequency distribution of naive and chronically infected skeletal muscle at day 0 (no CTX), 1, 4, and 10 after CTX-induced injury (n = 3 mice/group). (D) Average muscle fiber cross-sectional area at 10 days after CTX-induced injury in naive and infected mice (n ≥ 1,000 measurements/group from n = 4 mice/group). Results are representative of 3 experiments of n = 3–4/group/experiment; error bars represent SEM (C and D). ****P < 0.0001 by Kolmogorov-Smirnov (K-S) test (C) or Student’s t test (D).

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