The dual challenge: how age and diabetes shape leukocytes in distal limbs

Aims: A recent study by Nichols et al. examined age- and diabetes-related changes in leukocyte function in the distal limb before the onset of infection or ulceration using the Leprdb/db mouse — a well-established animal model of type 2 diabetes.

Methods: To gain additional insight into disease pathogenesis in the skin of the distal limb, the authors employed single-cell RNA-sequencing, intercellular communication analysis, as well as histological techniques in male Leprdb/db and their control LeprWT/WT littermates at 12 and 21 weeks of age.

Results: In addition to sensory loss, single-cell RNA-seq analysis revealed immune cell heterogeneity in the diabetic hindpaw, identifying 12 distinct leukocyte clusters at both 12 and 21 weeks of age. By 21 weeks, Leprdb/db mice displayed increased levels of mast cells/basophils, dermal γδ T cells, heterogeneous T cells, and type 2 innate lymphoid cells. Mapping leukocyte cell-cell communication identified significant dysregulation of both innate and adaptive immune cell signaling networks in the skin of diabetic animals at both ages. Sub-clustering of macrophages, the largest cluster, demonstrated a shift toward M2-like macrophages (marked by increased Lyve1 levels) in the hindpaws of diabetic mice. Histological analysis confirmed these findings, demonstrating that these cells were localized in the deep dermis near small and large blood vessels of the hind limb, with minimal association with the nerves.

Conclusions: Overall, these findings indicate that diabetic neuropathy, in conjunction with disease duration, is linked to substantial changes in both the population and function of multiple immune cell types over time. This may explain the increased susceptibility to distal limb pathologies in patients with chronic diabetes.

Comments. The study by Nichols et al. offers valuable insights into the early immune alterations that may predispose diabetic patients to distal limb complications. The findings emphasize the impact of disease duration on immune cell functionality, particularly the emergence of M2-like macrophages, which generally contribute to tissue repair and anti-inflammatory functions. However, additional studies are required to clarify whether this shift in macrophage phenotype under chronic diabetes conditions could lead to maladaptive responses and worsen the vascular disturbances observed in diabetic neuropathy. Overall, this research highlights the importance of immune cell dynamics on the distal presentation of diabetic neuropathy and underscores the need for further exploration to translate these findings to clinical settings.

Stéphanie Eid

Reference. Nichols JM, Pham HV, Lee EF, Mahalingam R, Shepherd AJ. Single-cell analysis of age-related changes in leukocytes of diabetic mouse hindpaws. Cell Mol Life Sci. 2024 Mar 19;81(1):146. doi: 10.1007/s00018-024-05128-z. PMID: 38502310; PMCID: PMC10951029.

https://link.springer.com/article/10.1007/s00018-024-05128-z