Introduction

What is crohn’s disease?

Crohn's disease (CD) is a chronic inflammatory condition of the gastrointestinal tract, characterised by periods of flare-ups and remission. It primarily affects the ileum but can involve any part of the GI tract from mouth to anus. There are many factors contributing to the cause of CD, including genetic, environmental, and immunological factors​.^1,2 The frequency of CD in the population is rising globally, particularly in developed countries, affecting millions of people.

CD inflammation is typically transmural, meaning it affects all layers of the bowel wall, leading to complications like strictures, fistulas, and abscesses. The inflammation is patchy, with segments of healthy tissue interspersed between affected areas, creating a "skip lesion" pattern.^1,2 This chronic inflammation can result in severe abdominal pain, diarrhoea, weight loss, and malnutrition, significantly impaired quality of life.

The importance of monocytes in CD

Monocytes are crucial components of the innate immune system. They circulate in the blood and move into tissues where they differentiate into macrophages and dendritic cells, playing a pivotal role in phagocytosis, antigen presentation, and cytokine production. These cells are vital to the body's defence against pathogens and in maintaining immune homeostasis​.^1,2 

Monocytosis, an elevated level of monocytes in the blood, is a notable feature in inflammatory bowel disease (IBD), including CD. Studies indicate that patients with CD often have increased monocyte counts, although this elevation does not always correlate with disease activity.¹ Monocytes contribute to the inflammatory milieu of CD by differentiating into pro-inflammatory macrophages that move into the intestinal mucosa, making inflammation and tissue damage worse.² This continued recruitment and activation of monocytes and macrophages underscore their significance in the pathophysiology of CD, marking them as potential targets for therapeutic intervention.

Causes of monocytosis in crohn's disease

Immune response and inflammation

In CD, the immune system responds to intestinal inflammation by recruiting monocytes to the site of injury. Monocytes are attracted to inflamed tissues through chemokines and adhesion molecules expressed in the endothelium of blood vessels. The reshaping of the extracellular matrix and increased expression of molecules such as MAdCAM-1 help monocyte movement from the bloodstream into the intestinal mucosa. Once in the tissue, monocytes differentiate into macrophages and dendritic cells, which are pivotal in maintaining the inflammatory response​.^1,2

Cytokines play a crucial role in monocyte recruitment and activation in CD. Pro-inflammatory cytokines such as TNF-α, IL-12, and IL-23 are elevated in CD and drive the inflammatory response. These cytokines not only promote the differentiation of monocytes into macrophages and dendritic cells but also enhance their ability to produce additional pro-inflammatory cytokines, thus sustaining the inflammatory environment. The persistent cytokine signalling creates a feedback loop, driving the recruitment and activation of monocytes and other immune cells, leading to chronic inflammation.^2,3

What is the role of granulomas?

Monocytes are critical to the formation of granulomas. Upon migration to the site of inflammation, monocytes differentiate, or develop, into macrophages. These macrophages engulf pathogens and secrete cytokines, further recruiting immune cells to the granuloma. The constant influx and activation of monocytes and macrophages within the granulomas contribute to the persistent inflammation seen in CD. This process underscores the significance of monocytes in the pathogenesis of CD, as their continual recruitment and differentiation are central to both the formation and maintenance of granulomas.^1,3

Role of monocytes in crohn's disease

Differentiation and function

Monocytes are versatile cells that differentiate into macrophages and dendritic cells (DCs) upon migrating into tissues. In the context of CD, monocytes recruited to the intestinal mucosa differentiate into inflammatory macrophages and DCs. These cells play crucial roles in phagocytosis, antigen presentation, and the release of inflammatory mediators​.⁴ The differentiation process is influenced by the local cytokine milieu and interactions with other immune cells, which dictate the specific roles that these differentiated cells will play in the inflammatory response.^2,4

Monocytes contribute significantly to the inflammatory environment in CD by releasing a variety of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6. These cytokines not only sustain the inflammatory response but also recruit additional immune cells to the site of inflammation, thereby continuing the cycle of inflammation. The secretion of these cytokines by monocytes and their differentiated forms, macrophages and DCs, amplifies the immune response, leading to the characteristic chronic inflammation seen in CD​.⁴

Impact on disease pathogenesis

The continuous recruitment and activation of monocytes are key factors in the progression and severity of CD. Inflammatory macrophages derived from monocytes are known to produce high levels of pro-inflammatory cytokines, which make tissue damage worse and contribute to the formation of granulomas, a hallmark of CD.⁴ These granulomas further continue inflammation and can lead to complications such as strictures and fistulas. Thus, the activity of monocytes and their differentiated forms significantly influences the clinical course and severity of CD, highlighting their crucial role in disease pathogenesis​.^1,4

Diagnosis of monocytosis in crohn's disease

To measure monocyte levels, a complete blood count (CBC) is typically used. This test can quantify the total white blood cell count and identify the proportion and absolute number of monocytes present. Advanced techniques such as flow cytometry, which employs cytochemical staining for non-specific esterase, offer more precise identification and quantification of monocytes by distinguishing them from other leukocytes based on their unique enzymatic activity​.¹

In CD, elevated monocyte counts correlate variably with disease activity. While some studies show that monocyte levels are higher in patients with active CD compared to those in remission, the correlation is not always statistically significant.¹ Monocytes are recruited to sites of inflammation in the intestines, contributing to the local inflammatory response. This recruitment and subsequent activation are mediated by cytokines, such as TNF-α and IL-1β, which are also elevated in active CD. Consequently, monocyte levels can serve as an indirect marker of inflammation.

Other biomarkers like C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are also elevated in response to inflammation and are often measured alongside monocyte counts to assess disease activity and severity. These markers provide a broader picture of the inflammatory state and are used to monitor the effectiveness of therapeutic interventions. Elevated CRP and ESR levels generally correlate with higher disease activity, offering a valuable tool for clinicians in managing CD.^3,5

By integrating monocyte counts with these additional biomarkers, healthcare providers can better understand the inflammatory landscape of CD, aiding in the diagnosis, monitoring, and management of the disease.

Therapeutic approaches targeting monocytes ​

Current treatments

Corticosteroids, such as prednisone, are commonly used to reduce inflammation in CD by suppressing the immune system. They decrease the recruitment and activation of monocytes, thereby reducing the inflammatory response in the gastrointestinal tract. However, long-term use of corticosteroids is limited due to significant side effects, including increased risk of infection and bone loss​.⁶

Immunosuppressants, such as azathioprine and methotrexate, are also employed to control CD. These drugs work by inhibiting the proliferation of immune cells, including monocytes, and reducing the production of pro-inflammatory cytokines. By limiting monocyte activity and differentiation into macrophages and dendritic cells, immunosuppressants help control chronic inflammation in CD.⁶

Emerging therapies

Emerging therapies are focusing on more specific targets within the immune system to manage CD more effectively and with fewer side effects. Biologics, such as anti-TNF agents (e.g., infliximab), directly target cytokines involved in the inflammatory response. These biologics inhibit TNF-α, a key cytokine produced by monocytes and macrophages, thus reducing inflammation and improving clinical outcomes in many CD patients.⁶

Janus kinase (JAK) inhibitors are another promising class of drugs. These small molecules block the signalling pathways of various cytokines, including those involved in monocyte activation and differentiation. By inhibiting JAK, these drugs reduce the inflammatory response at a molecular level, offering a novel approach to managing CD.⁶

Conclusion

In summary, monocytosis plays a pivotal role in the pathogenesis and progression of CD. Elevated monocyte levels contribute to chronic inflammation through their differentiation into macrophages and dendritic cells and their significant cytokine release. These processes perpetuate the inflammatory cascade, influencing disease severity and progression. Understanding the role of monocytes in CD highlights their potential as both biomarkers for disease activity and targets for therapeutic intervention.

The implications for future research and clinical practice are profound. Current treatments, including corticosteroids and immunosuppressants, as well as emerging therapies like biologics and JAK inhibitors, show promise in targeting monocyte activity. However, the variable response to these treatments underscores the need for personalized medicine approaches in managing CD.

Future directions should focus on further studies to elucidate the precise mechanisms of monocyte involvement in CD. Investigating the efficacy of therapies specifically targeting monocytes and their signalling pathways could lead to more effective and tailored treatment strategies. Such research is essential to improve patient outcomes, reduce disease burden, and enhance the overall management of CD. By advancing our understanding of monocyte biology in CD, we can pave the way for novel therapeutic approaches and better clinical practices