Macrophage Dynamics in Renal Injury and Repair

Macrophages exhibit remarkable plasticity, playing pivotal roles in the initiation, progression and resolution of renal injury. In the acute phase, circulating monocytes infiltrate injured renal parenchyma and differentiate into classically activated (M1) macrophages that release pro-inflammatory mediators, clear debris and orchestrate the early immune response. As tissue repair commences, a shift towards alternatively activated (M2) macrophages promotes anti-inflammatory cytokine secretion, extracellular matrix remodelling and angiogenesis. Resident macrophage populations of embryonic origin self-renew in situ and contribute to homeostasis, while bone-marrow-derived macrophages dynamically replenish niches after severe injury. Dysregulated transitions between these phenotypes can precipitate chronic inflammation, fibrosis and loss of renal function. Recent advances in single-cell genomics and lineage tracing have refined our understanding of macrophage subsets, their metabolic states and intercellular crosstalk with tubule epithelial cells, neutrophils and T cells. Therapeutic modulation of macrophage recruitment, polarisation and effector pathways now emerges as a promising strategy to mitigate acute kidney injury and to prevent the progression to chronic kidney disease.

Research from Nature Portfolio

Genetic ablation and pharmacological inhibition of haematopoietic cell kinase (HCK) have been demonstrated to attenuate macrophage M1-like activation through restoration of autophagic flux, thereby reducing inflammation and fibrosis in models of unilateral ureteral obstruction and ischaemia–reperfusion injury. A selective HCK inhibitor decreased macrophage recruitment and pro-inflammatory cytokine release, ameliorating renal scarring. Another study has compared two waves of macrophage infiltration after acute ischaemic injury, revealing that persistent macrophage populations sustain a pro-inflammatory milieu, recruiting neutrophils and T cells that drive tubule atrophy. Temporary depletion of these late-phase macrophages interrupted the T-cell- and neutrophil-mediated cycle of injury, highlighting a temporal window for immunomodulatory intervention to enhance tubular repair.

Macrophage Dynamics in Renal Injury and Repair publication trend

The graph below shows the total number of articles in macrophage dynamics in renal injury and repair across all publications each year (not limited to Nature Index journals).

Technical terms

Macrophage polarisation: The process by which macrophages adopt distinct functional phenotypes, broadly categorised as pro-inflammatory (M1) or anti-inflammatory and pro-repair (M2).

Ischaemia–reperfusion injury: Tissue damage caused when blood supply returns to the kidney after a period of oxygen deprivation, triggering inflammation and oxidative stress.

Autophagy: A cellular degradation pathway that removes damaged organelles and proteins, regulating macrophage activation and survival.

Kidney-resident macrophages: Long-lived macrophages of embryonic origin residing in the renal parenchyma, contributing to homeostasis and early injury responses.

Insulin-like growth factor 1 (IGF1): A cytokine produced by macrophages that promotes cell proliferation and survival via the AKT/Rb signalling pathway.

References

1. HCK induces macrophage activation to promote renal inflammation and fibrosis via suppression of autophagy. Nature Communications (2023).
2. Mrc1+ macrophage-derived IGF1 mitigates crystal nephropathy by promoting renal tubule cell proliferation via the AKT/Rb signaling pathway. Theranostics (2024).
3. Single Cell RNA Sequencing Identifies a Unique Inflammatory Macrophage Subset as a Druggable Target for Alleviating Acute Kidney Injury. Advanced Science (2022).
4. Distinct fate, dynamics and niches of renal macrophages of bone marrow or embryonic origins. Nature Communications (2020).
5. Macrophage Heterogeneity in Kidney Injury and Fibrosis. Frontiers in Immunology (2021).
6. Immune-mediated tubule atrophy promotes acute kidney injury to chronic kidney disease transition. Nature Communications (2022).