Macrophage Phenotype in Diabetic Wound Healing - European Medical Journal

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Macrophage Phenotype in Diabetic Wound Healing

1 Mins
Diabetes
Authors:
Ioanna Eleftheriadou,1 Anastasios Tentolouris,1 Ioanna Anastasiou,1 Dimitrios Tsilingiris,1 Ourania Kosta,1 Evangelia Tzeravini,1 Ioannis Pateras,2 *Nikolaos Tentolouris1

1. First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
2. Department of Histology–Embryology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
*Correspondence to [email protected] 

Disclosure:

The authors have declared no conflicts of interest.

Acknowledgements:

The authors would like to thank Maria Maragkoula, Assoc Prof Konstantinos Evangelou, and Prof Vassilis G. Gorgoulis for their valuable help at the Laboratory of Histology-Embryology in Medical School, National and Kapodistrian University of Athens, Athens, Greece.

Citation:
EMJ Diabet. ;8[1]:48-50. Abstract Review No: AR7.
Keywords:
Diabetes, inflammation, macrophage phenotype, wound healing.

Each article is made available under the terms of the Creative Commons Attribution-Non Commercial 4.0 License.

BACKGROUND

Diabetic foot ulcers (DFU) are usually chronic wounds that present in the inflammatory phase of the wound healing process.1 In the early inflammation phase, proinflammatory or classically activated (M1) macrophages secrete proinflammatory cytokines and ‘clean’ the ulcer by phagocytosing bacteria and debris. As the inflammation resides, macrophages undergo a transition to an anti-inflammatory and healing phenotype (M2 or alternatively activated macrophages).1,2,3 Diabetic animal wound studies have shown a delayed macrophage phenotype transition and an increased M1/M2 macrophage ratio.4,5,6The aim of the current study was to examine the macrophage phenotype in the skin of patients with diabetes with and without DFU, and to look for potential differences in skin macrophages in the forearm and foot of patients with DFU.

METHOD

A total of 20 patients with diabetes (10 with chronic noninfected DFU and 10 without DFU) and 12 healthy controls were recruited. Forearm 3 mm skin punch biopsies were obtained from all participants. In addition, punch biopsies from the borders of the foot ulcers were obtained from patients with DFU. Skin biopsies were fixed in formaldehyde, embedded in paraffin, and sections were cut for immunohistochemistry. Cluster of differentiation (CD)64 was used as a marker for the identification of M1 macrophages and CD163 as a marker of M2 macrophages. The ankle–brachial index was measured and values ≤0.90 were considered indicative of peripheral arterial disease, while diabetic peripheral neuropathy diagnosis was based on neuropathy symptom score and neuropathy disability score.

RESULTS

The three groups of participants did not differ in terms of age and sex. The two diabetic cohorts did not differ in terms of diabetes duration and glycaemic control. None of the participants had peripheral arterial disease, while all patients with DFU and nine patients (90%) with diabetes without DFU had diabetic peripheral neuropathy. The number of CD64+ and CD163+ cells from the forearm biopsies differed significantly between the three groups of participants (Table 1); subanalysis showed that patients with DFU had significantly higher numbers of CD64+ cells when compared with patients without DFU and healthy participants. Participants with DFU and without DFU had significantly higher numbers of CD163+cells when compared with healthy individuals in the forearm biopsies. The number of CD64+ and CD163+cells did not differ between the forearms and feet of patients with DFU: 5.8 (5.3, 6.4) versus 6.0 (5.5, 11.7), p=0.139; and 6.5 (5.2, 7.5) versus 7.0 (4.5, 8.3), p=1.000, respectively.

Table 1: CD64 and CD163 positive cells in forearm biopsies.
*p values for comparisons between all three groups by Kruskal–Wallis H test.
†p values for comparisons between pairs of groups (1 vs 2, 1 vs 3, and 2 vs 3) by Mann–Whitney U test.
CD: cluster of differentiation; DFU: diabetic foot ulcers; DM: diabetes mellitus; vs: versus.

CONCLUSION

There was increased inflammation in the skin of patients with DFU when compared with patients with diabetes without DFU, and with healthy individuals. In the forearms and feet of individuals with DFU, similar macrophage phenotype, which is associated with a chronic proinflammatory state, was observed. This notion could suggest that increased inflammation in the skin of patients with diabetes either results in foot ulceration, or impairs normal wound healing.Further, larger clinical studies are needed to clarify whether inflammatory cytokine inhibition or modification of macrophage phenotype could be a promising therapeutic approach for chronic refractory DFU.

References
Baltzis D et al. Pathogenesis and treatment of impaired wound healing in diabetes mellitus: new insights. Adv Ther. 2014;31(8):817-36. Krzyszczyk P et al. The role of macrophages in acute and chronic wound healing and interventions to promote pro-wound healing phenotypes. Front Physiol. 2018;9:419. Kim SY et al. Macrophages in wound healing: activation and plasticity. Immunol Cell Biol. 2019;97(3):258-67. Tellechea A et al. Increased skin inflammation and blood vessel density in human and experimental diabetes. Int J Low Extrem Wounds. 2013;12(1):4-11. Pradhan Nabzdyk I et al. Expression of neuropeptides and cytokines in a rabbit model of diabetic neuroischemic wound healing. J Vasc Surg. 2013;58(3):766-5. Mirza RE et al. Blocking interleukin-1 beta induces a healing-associated wound macrophage phenotype ad improves healing in type 2 diabetes. Diabetes. 2013;62(7):2579-87.

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